Central respiratory effects on motor nerve activities after organophosphate exposure in a working heart brainstem preparation of the rat

• Published in: Toxicology letters Vol. 206; no. 1; pp. 94 - 99
• Main Authors: Klein-Rodewald, Tanja, Seeger, Thomas, Dutschmann, Mathias, Worek, Franz, Mörschel, Michael
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Shannon Elsevier Ireland Ltd 25.09.2011; Elsevier
• Subjects: acetylcholine; acetylcholinesterase; Acetylcholinesterase - metabolism; Animals; apnea; Asphyxia - physiopathology; Biological and medical sciences; brain stem; Brain Stem - drug effects; Brain Stem - enzymology; Brainstem; breathing; Crotylsarin; Female; heart; Heart - drug effects; Heart - innervation; Heart - physiology; Hypoglossal Nerve - drug effects; Hypoglossal Nerve - physiology; In Vitro Techniques; Medical sciences; Motor Neurons - drug effects; Motor Neurons - physiology; nerve tissue; Organophosphorus compound; Perfusion; Peripheral Nerves - drug effects; Peripheral Nerves - physiology; Phrenic nerve; Phrenic Nerve - drug effects; Phrenic Nerve - physiology; poisoning; Rats; Rats, Sprague-Dawley; Respiratory control; Respiratory Muscles - drug effects; Respiratory Muscles - innervation; Respiratory Rate - drug effects; Respiratory Rate - physiology; Sarin - analogs & derivatives; Sarin - toxicity; Toxicology; Vagus Nerve - drug effects; Vagus Nerve - physiology; Crotylsarin; Phrenic nerve; Respiratory control; Brainstem; Organophosphorus compound; Heart; Rat; Brain stem; Rodentia; Central nervous system; Exposure; Respiratory system; Encephalon; Vertebrata; Mammalia; Animal; Motor nerve; Organophosphorus compounds; Circulatory system; Motricity
• ISSN: 0378-4274; 1879-3169; 1879-3169
• DOI: 10.1016/j.toxlet.2011.07.005

► We established the use of rat working heart brainstem preparation (WHBP) for investigation of organophosphorus compounds (OPs). ► We recorded transient central respiratory depression after exposure to an OP. ► This effect was aggravated by simultaneous hypo-perfusion. ► Brain acetylcholinesterase inhibition was obviously compensated by intrinsic rescue mechanisms. ► The impact of organophosphorus compound (OP) intoxication on the activity of central respiratory circuitry, causing acetylcholinesterase (AChE) inhibition and accumulation of acetylcholine in the respiratory brainstem circuits, is not understood. We investigated the central effect of the OP Crotylsarin (CRS) on respiratory network activity using the working heart brainstem preparation, which specifically allows for the analysis of central drug effects without changes in brainstem oxygenation possibly caused by drug effects on peripheral cardio-respiratory activity. Respiratory network activity was determined from phrenic and hypoglossal or vagal nerve activities (PNA, HNA, VNA). To investigate combined central and peripheral CRS effects hypo-perfusion was used mimicking additional peripheral cardiovascular collapse. Systemic CRS application induced a brief central apnea and complete AChE-inhibition in the brainstem. Subsequently, respiration was characterised by highly significant reduced PNA minute activity, while HNA showed expiratory related extra bursting indicative for activation of un-specified oro-pharyngeal behaviour. During hypo-perfusion CRS induced significantly prolonged apnoea. In all experiments respiratory activity fully recovered after 1 h. We conclude that CRS mediated AChE inhibition causes only transient central breathing disturbance. Apparently intrinsic brainstem mechanisms can compensate for cholinergic over activation. Nevertheless, combination of hypo-perfusion and CRS exposure evoke the characteristic breathing arrests associated with OP poisoning.